The present invention relates to new derivatives of erythromycin, their preparation process and their use as medicaments.
A subject of the invention is the compounds of formula 
in which
Y represents a hydrogen atom or a fluorine atom,
n represents an integer comprised between 1 and 8,
Z represents a hydrogen atom or the remainder of a carboxylic acid,
optionally substituted on the heterocyle by one or more alkyl, alkenyl, alkynyl, O-alkyl, O-alkenyl, O-alkynyl, S-alkyl, S-alkenyl, S-alkynyl radicals containing up to 8 carbon atoms, one or more OH, NH2, Cxe2x95x90N, NO2, CF3 radicals or one or more aryl radicals containing up to 14 carbon atoms or heteroaryl radicals containing one or more nitrogen oxygen or sulphur atoms, the aryl or heteroaryl radicals themselves being able to be substituted as well as their addition salts with acids.
As an example of the addition salts of the present derivatives with mineral or organic acids, the salts formed with acetic, propionic, trifluoroacetic, maleic, tartaric, methanesulphonic, benzenesulphonic, p-toluenesulphonic, hydrochloric, hydrobromic, hydroiodic, sulphuric, phosphoric acids and especially stearic, ethylsuccinic or laurylsulphonic acids can be mentioned.
In the definition of the substituants, the alkyl, alkenyl or alkynyl radical is preferably a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, decyl or dodecyl, vinyl, allyl, ethynyl, propynyl, propargyl, cyclobutyl, cyclopentyl or cyclohexyl radical.
The aryl radical can be a phenyl or naphthyl radical.
The substituted or non substituted heteroaryl radical can be a thienyl, furyl, pyrolyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, pyrazolyl or isopyrazolyl radical, a pyridyl, pyrimidyl, pyridazinyl or pyrazinyl radical or also an indolyl, benzofurannyl, benzothiazyl or quinolinyl radical. These aryl radicals can contain one or more substituants chosen from the groups mentioned above.
A quite particular subject of the invention is the compounds of formula (I) in which Z represents a hydrogen atom, those in which n represents the number 4, those in which the 
radical is substituted by a 
radical.
A more particular subject of the invention is the compounds of formula (I) in which Y represents a hydrogen atom.
Among the preferred compounds, the compounds whose preparation is given here after in the experimental part can particularly be mentioned and more particularly the compound of Example 1
The products of general formula (I) have a very good antibiotic activity on gram⊕ bacteria such as staphylococci, streptococci, pneumococci.
The compounds of the invention can therefore be used as medicaments in the treatment of germ-sensitive infections and in particular, in that of staphylococcia such as staphylococcal septicaemias, malignant staphylococcia of the face or skin, pyodermitis, septic or suppurating wounds, boils, anthrax, phlegmons, erysipelas and acne, staphylococcia such as primitive or post-influenzal acute angina, bronchopneumonia, pulmonary suppuration, streptococcia such as acute angina, otitis, sinusitis, scarlatina, pneumococcia such as pneumonia, bronchitis, brucellosis, diphtheria, gonococcal infection
The products of the present invention are also active against infections caused by germs such as Haemophilus influenzae, Rickettsia, Mycoplasma pneumoniae, Chlamydia, Legionella, Ureaplasma, Toxoplasma, or germs of the Mycobacterium genus.
Therefore, a subject of the present invention is also the products of formula (I) as defined above, as well as their addition salts with the pharmaceutically acceptable mineral or organic acids, as medicaments and, in particular antibiotic medicaments.
A more particular subject of the invention is the product of Example 1 and its pharmaceutically acceptable salts, as medicaments and, in particular antibiotic medicaments.
A subject of the invention is also the pharmaceutical compositions containing at least one of the medicaments defined above, as active ingredient.
These compositions can be administered by buccal, rectal, parenteral route, or by local route as a topical application on the skin and mucous membranes, but the preferred administration route is the buccal route.
They can be solids or liquids and be presented in the pharmaceutical forms commonly used in human medicine, such as for example, plain or sugar-coated tablets, gelatin capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared according to the usual methods. The active ingredient or ingredients can be incorporated with the excipients usually used in these pharmaceutical compositions such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.
These compositions can also be presented in the form of a powder intended to be dissolved extemporaneously in an appropriate vehicle, for example, apyrogenic sterile water.
The dose administered is variable according to the affection treated, the patient in question, the administration route and the product considered. It can be, for example, comprised between 50 mg and 3000 mg per day by oral route for an adult for the product of Example 1.
A subject of the invention is also a preparation process characterized in that a compound of formula (II) 
in which Y retains its preceding meaning and M represents the remainder of an acid is subjected to the action of a compound of formula (III) 
in which the heterocyclic radical can be substituted in order to obtain the compound of formula (IA) in which Z represents the remainder of an acid, then if desired this compound of formula (IA) is subjected to the action of an agent which releases hydroxyl in position 2xe2x80x2 in order to obtain the corresponding compound of formula (IB) in which Z represents a hydrogen atom which if desired is subjected to the action of an acid in order to form the salt,
the reaction of the compound of formula (II) with the compound of formula (III) takes place in a solvent such as for example acetonitrile, dimethylformamide or also tetrahydrofuran, dimethoxyethane or dimethylsulphoxide,
the hydrolysis of the ester function in position 2xe2x80x2 is carried out using methanol or aqueous hydrochloric acid,
the salification is carried out using acids according to standard processess.
The compounds of formula (II) in which Y represents a hydrogen atom, used as starting products are described and claimed in the European Patent Application 0 596 802.
The compounds of formula (II) in which Y represents a fluorine atom can be prepared as indicated hereafter in the experimental part.